light must be high for the to be seen, which reduces Editorials the step increase induced by the penlight).6 If the pupillary light amplitude is less than 0.3 mm and the maximum constriction velocity is less than 1 mm/s, the reflex is unable to be detected using a The in penlight.6 In conscious patients with Holmes-Adie and Argyll-Robertson with ‘absent’ pupillary light the critically ill patient , small light reflexes have been detected using infrared pupillometry.7 Also in post-resuscitation non- brain dead critically ill patients with ‘absent’ pupillary The to light is controlled by the reflexes, the reflex has been demonstrated using a . The direct pupillary light portable infrared pupillometer.6 reflex refers to that occurs in the stimulated ; In this issue of Critical Care and Resuscitation, the consensual pupillary light reflex refers to miosis that Thomas8 describes a case of Guillain Barré syndrome occurs in the other eye. The reflex has a latent period presenting with weakness and fixed dilated pupils who with length of the period, amplitude of the response, and subsequently became ‘locked in’ with absence of any the speed of the pupillary constriction dependent on the clinical response to external stimuli. A positive brain intensity of the stimulus employed.1 For the reflex to be stem auditory evoked response was used to indicate truly tested, an intense stimulus and close observation normal brain stem function. In another recent report, a are required. The reflex has afferent, efferent and central case of ‘reversible fixed dilated pupils’ was associated connections; therefore non-response to light (i.e. reflex with carbamazepine and venlafaxine overdosage.9 Both iridoplegia) indicates a disturbance in one or all of these reports highlight the importance of the reflex and connections. together probably give the reader a complete list of the As areas in the controlling consciousness common and rare causes of ‘fixed dilated pupils’. are anatomically adjacent to the autonomic fibres However, from recent reports it would appear that some controlling the pupillary responses, the pupillary light of these conditions might be associated with ‘clinically reflex is a valuable guide to the presence and location of undetectable’ rather than ‘absent’ pupillary light brainstem diseases causing . Moreover, because reflexes. the pupillary response is relatively resistant to metabolic insult, the presence or absence of the light reflex is often Dr. L. I. G. Worthley used as the single and most important physical sign to Department of Critical Care Medicine distinguish a structural (i.e. potentially irreversible) Flinders Medical Centre from a metabolic (i.e. reversible) cause of coma. With SOUTH AUSTRALIA 5042 brainstem destruction the is lost whereas the size of the may change (albeit REFERENCES slowly),2 thus the ‘fixed’ element is more important 1. Ellis CJ. The pupillary light reflex in normal subjects. Br than the ‘dilated’ element in the clinical sign of ‘fixed J Ophthalmol 1981;65:754-759. dilated pupils’ 2. Ishiguro T, Tamagawa S, Ogawa H. Changes of pupil Although interobserver agreement on the presence size in brain death patients. Seishin Shinkeigaku Zasshi or absence of the light reflex is one of the most 1992;94:864-873. consistent measures of brain-stem function, 3. Teasdale G, Knill-Jones R, van der Sande J. Observer approximately 30% disagreement exists regarding the variability in assessing impaired consciousness and status of this reflex in comatose patients.3,4,5 The coma. J Neurol Neurosurg Psychiatry 1978;41:603-610. interobserver disagreement arises partially from the lack 4. van den Berge JH, Schouten HJ, Boomstra S, van Drunen Littel S, Braakman R. Interobserver agreement of a standard method to elicit the reflex. Traditionally in assessment of ocular signs in coma. J Neurol the pupillary light reflex is determined using a penlight Neurosurg Psychiatry 1979;42:1163-1168. (i.e. pencil torch) and factors such as the amount of 5. Wilson SF, Amling JK, Floyd SD, McNair ND. ambient light in the room, the observer’s visual acuity, Determining interrater reliability of nurses' assessments the distance of the penlight bulb from the patient’s pupil of pupillary size and reaction. J Neurosci Nurs and strength of the penlight batteries can alter the 1988;20:189-192. validity of the visual assessment of the reflex. The 6. Larson MD, Muhiudeen I. Pupillometric analysis of the reflex is also more difficult to detect with a wide pupil ‘absent light reflex’. Arch Neurol 1995;52:369-372. (e.g. a 0.2 mm reflex in a 5 mm diameter pupil is only a 7. Loewenfeld IE. syndromes. In: The Pupil: Anatomy, Physiology, and Clinical Applications. 4% reflex, whereas the same reflex in a 2 mm diameter Detroit, Michigan: Wayne State University Press. pupil is a 10% reflex) and in a dark iris (as the ambient 19931:956-1001.

7 EDITORIALS Critical Care and Resuscitation 2000; 2: 7-13

8. Thomas PD. The differential diagnosis of fixed dilated models of meningitis9 and some patients with traumatic pupils: a case report and review. Critical Care and brain injury, pressure flow-autoregulation is markedly Resuscitation 2000;2:34-37. impaired with no ability to defend Q& in face of 9. Cordova S, Lee R. Fixed, dilated pupils in the ICU: another recoverable cause. Anaesth Intensive Care changing Pi. Using endotoxin as a model of sepsis, there 2000;28:91-93. also appears to be a left shift of the renal autoregulation curve.10,11 Although this results in an elevated Q& at a given Pi, when this falls the steeper pressure-flow curve Haemodynamic targets in results in greater falls in renal Q& . Taken together, these data suggest that from the perspective of these organs, shock: choosing a pressure blood pressure must be defended to at least a mean of 80 mmHg. While differences in outcome have not been demonstrated, this is supported both by studies In his comprehensive review of shock, Worthley1 demonstrating increases in Q& with vasopressors such as reminds us that despite the knowledge explosion noradrenaline or , and by many anecdotal regarding its possible mediators, this has not yet series. However, since there is a range of autoregulatory translated into clinically useful therapeutic intervent- thresholds in the normal population 80 mmHg may be ions. Consequently, haemodynamic resuscitation higher than necessary in some patients, but insufficient remains central to management. While it is clear that in others. Finally, since high doses of these agents may many manifestations of shock are not simply due to the right shift the pressure-flow curve demanding a higher effects of inadequate nutritional blood flow ( Q& ), this is blood pressure to maintain Q& , these drugs must be often a precipitating and compounding factor leading to carefully titrated. organ dysfunction and death. However, optimization It is also important to consider metabolically active and augmentation of regional Q& remains polemic, often tissues such as muscle which also depend upon pressure resulting in arguments surrounding adequacy of to maintain Q& when vasodilator reserve is no longer perfusion pressure, systemic Q& , and specific regional available. For example, in the ischaemic dog heart Braunwald and coworkers12 found that isoprenaline, vascular effects of drugs. Regional Q& is determined by dobutamine and nitroglycerine infusions resulted in a the inflow pressure (Pi), the outflow pressure (Po), and worsening of ischaemia and function because changes the regional conductance (c): in myocardial work were not matched with changes in

coronary perfusion pressure. However, noradrenaline Q& = (Pi – Po) x c infusion improved myocardial contractility without worsening ischaemia since perfusion pressure increased. and while Po is often neglected or simply thought of as These data mimic that reported in patients with the regional venous pressure, Q& ceases at a Pi well cardiogenic shock,13 and while intra-aortic balloon above the venous pressure (often 30 - 40 mmHg). This counterpulsation achieves an increase in perfusion is termed the critical closing pressure of that organ, and pressure with a reduction in work, this may not be reflects both tissue pressure (which in turn will be appropriate in all patients. Similar data, emphasizing the influenced by venous pressure) and the smooth muscle importance of perfusion pressure through its defense tone of terminal arterioles and precapillary sphincters. with vasopressors resulting in improved function, have In organs such as the brain and kidney, with tight been reported both for the right ventricle14,15 during pressure-flow autoregulation, Q& falls once pressure is pulmonary hypertension, and the diaphragm during 16,17 reduced below their autoregulatory threshold. Pressure inspiration. reductions prior to that are compensated by a rise in Where then does this leave the clinician? Much of regional conductance, however, when the regional this data is from animal models or utilizes techniques vasodilator reserve is reached, flow falls linearly with not commonly available at the bedside. Properly pressure. controlled trials looking at a target blood pressure have In healthy subjects the autoregulatory threshold for not been performed and are unlikely to be at a high the brain is ∼85 mmHg; however this represents the priority. However, there does seem to be a reasonable body of data supporting a target mean blood pressure mean from a wide range (∼50 - 100 mmHg), and 1 patients with treated hypertension have a right shifted significantly greater than 60 mmHg. This may require the use of vasopressor catecholamines, but with the curve with their mean autoregulatory threshold ∼110 2,3 provisos that their use is titrated to clinical effect and mmHg. Although these data may seem high, similar that systemic flow is adequate, the risk:benefit ratio estimates have been published for the renal autoregulatory threshold.4,5,6 In acute renal failure,7,8 favours a consequent increase in regional Q& .

8 Critical Care and Resuscitation 2000; 2: 7-13 EDITORIALS

Dr. A. D. Bersten 17. Aubier M, Murciano D, Menu Y, Boczkowski J, Mal H, Department of Critical Care Medicine Pariente R. Dopamine effects on diaphragmatic strength Flinders Medical Centre during acute respiratory failure in chronic obstructive SOUTH AUSTRALIA 5042 pulmonary disease. Ann Intern Med 1989;110:17-23.

REFERENCES 1. Worthley LIG. Shock: A review of pathophysiology and management. Parts I & II. Critical Care Resuscitation The ANZICS clinical trials 2000;2:55-84. 2. Schmidt JF, Waldemar G, Vorstrup S, Andersen AR, group Gjerris F, Paulson OB. Computerized analysis of cerebral blood flow autoregulation in humans: validation of a method for pharmacologic studies. J Cardiovasc There has been a growing perception that a powerful Pharmacol 1990;15:983-988. way to advance the quality of practice in Critical Care 3 Larsen FS, Olsen KS, Hansen BA, Paulson OB, Medicine is through the increasing application of the Knudsen GM. Transcranial Doppler is valid for concepts of Evidence Based Medicine (EBM).1 determination of the lower limit of cerebral blood flow However, intensive care units (ICUs) have a limited autoregulation. Stroke 1994:10:1985-1988. throughput of patients (typically no more than 4. Kircheim HR, Ehmke H, Hackenthal R, et al. 2000/year) and an extraordinarily heterogeneous patient Autoregulation of renal blood flow, glomerular filtration rate and renin release in conscious dogs. Pflugers Arch population. Furthermore, such patients undergo a 1987;410:441-449. myriad of interventions every day and the effects of 5. Schmid HE, Garrett RC,Spencer MP. Characteristics of therapeutic maneuvers on patient outcome are difficult pressure-flow autoregulation by the kidney. J Appl to discern, except for extreme situations. Physiol 1962;17:201-204. The combination of confounding variables, limited 6. Stone AM, Stahl WM. Renal effects of hemorrhage in numbers, patient heterogeneity, urgency of treatment normal man. Ann Surg 1970;172:825-836. and heuristic bias pose serious obstacles to the gathering 7. Adams PL, Adams FF, Bell PD, et al. Impaired renal of high-quality evidence upon which to base our clinical blood flow autoregulation in ischemic acute renal practice.2 failure. Kidney Int 1980;18:68-76. 8. Kelleher SP, Robinette JB, Conger JD. Sympathetic One possible response to such significant logistic nervous system in the loss of autoregulation in acute difficulties would be to accept defeat and to continue to renal failure. Am J Physiol 1984;246:F379-386. practice on the basis of physiological reasoning, 9. Tureen JH, Dworkin RJ, Kennedy SL, et al. Loss of experience, mentorship, local folklore and personal bias. cerebrovascular autoregulation in experimental Many Australasian intensivists, however, feel in rabbits. J Clin Invest 1990;85:577-581. uncomfortable with such defeatist attitudes and believe 10. Bersten AD. Renal autoregulation during sepsis, and that much can be achieved if resources are pooled and a infusion of catecholamines. Shock 1995;4:S25. commitment is made to the process of gathering 11. Bellomo R, Kellum JA, Wisniewski SR, Pinsky MR. evidence through randomised controlled studies. These Effects of norepinephrine on the renal vasculature in normal and endotoxemic dogs. Am J Respir Crit Care clinicians have progressively gathered momentum and Med 1999;159:1186-1192. organisational strength over the last five years and are 12. Vatner SF, McRitchie RJ, Maroko PR, Patrick TA, now steadily making progress under the banner of the Braunwald E. Effects of catecholamines, exercise, and ANZICS Clinical Trials Group (CTG). This group, nitroglycerin on the normal and ischemic myocardium in which first met in 1994 in Sydney, has published its first conscious dogs. J Clin Invest 1974;54:653-575. epidemiological study3 and has recently completed its 13. Mueller H, Ayres SM, Gregory JJ, Giannelli S, Grace first double-blind randomised controlled trial. This trial WJ. Hemodynamics, coronary blood flow, and compared low-dose dopamine with placebo for renal myocardial metabolism in coronary shock; response to l- rescue in patients with early renal dysfunction and norepinephrine and isoproterenol. J Clin Invest 1970;49:1885-1902. involved 328 patients in 23 units. It has just been 14. Vlahakes GJ, Turley K, Hoffman IE. The submitted for publication. pathophysiology of failure in acute right ventricular As the CTG has progressed in its efforts, it has also hypertension: Hemodynamic and biochemical grown in membership and organisation. It held its first correlations. Circulation 1981;63:87-95. separate meeting in Noosa in 1999 and will be holding 15. Molloy WD, Lee KY, Girling L, et al. Treatment of its second yearly meeting in Surfers Paradise on April shock in a canine model of pulmonary embolism. Am 15 and 16, 2000. It now has a web site Rev Respir Dis 1984;130:870-874. (http://anzics.herston.uq.edu.au/zindex.html) and an 16. Supinski GS, DiMarco AF, Gonzalez J, et al. Effect of executive. Membership remains open to all interested norepinephrine on diaphragmatic fatigue. J Appl Physiol 1990;69:2019-2028. physicians and nurses.

9 EDITORIALS Critical Care and Resuscitation 2000; 2: 7-13

The growth in membership and organisation has come hand in hand with an increase in its activities and Microwave warming of in the scope of its goals. A large multicentre epidemiological study of the incidence and outcome of fluids - pH and other sepsis in Australian and New Zealand ICUs has just been completed and data entry is under way. To our questions knowledge, this is the largest prospective study of this kind in the world. Similarly, another epidemiological study of the incidence, treatment and outcome of acute In this issue of Critical Care and Resuscitation, Drs lung injury/acute respiratory distress syndrome Steele and Story investigate whether microwave heating of 0.9% saline packaged in standard polyvinyl chloride (ALI/ARDS or the ALIve study) has just been 1 completed in 3 Australian States involving all such (PVC) bags changes pH. They heated 1 litre and 100 patients over a predetermined time period. Preliminary mL bags to unspecified temperatures in an 800 watt data will be presented in April 2000. April 2000 is also oven on the ‘high’ setting for 2 minutes and 30 seconds the starting time for the respectively and found that the pH of the saline epidemiology study, another ambitious project that, measured the next day at ambient temperature was the together with the sepsis and ALI studies will allow us to same as that of unheated controls. However there was a plan future interventional trials. Finally, an enormous statistically significant difference in pH between the 1 organisational effort is now under way involving 90 litre bag specimens (pH ∼ 5.0 for both heated and clinicians, 13 large ICUs and the Institute for control bags) and the 100 mL specimens (pH ∼ 4.6). International Health. This effort is aimed at conducting Although it was not possible to incriminate microwave the largest randomised, double-blind controlled ICU heating, the authors speculate that this pH discrepancy study so far, a study which will test the efficacy and might have been caused by acids released from the PVC safety of resuscitation with 4% albumin. packaging in differing amounts due to the different The growth of the CTG has also gone hand in hand surface area to volume ratios of the 1 litre and 100 mL with the growth of the ICU Foundation. The two bags. They suggest that such products of PVC organisations, with the continuing support and degradation might include the plasticiser di(2- encouragement of the ANZICS Board, have developed a ethylhexyl) phthalate (DEHP), as well as formic and symbiotic relationship in which fund raising, trial acetic acids. However, none of these compounds were design, goal setting and strategy development have assayed in their experiment. become a continuing process. Are these valid suggestions? The finding of an acid I believe there has never been a more exciting time pH is no surprise in itself, despite the fact that NaCl for those who can see the advantages of EBM and the solutions in pure water have a neutral pH. Many extraordinary benefits of collaborative work. Indeed, it crystalloids prepared commercially for infusion are is possible that, because of these efforts, in the next 5 known to have an acidic pH. For example, in one study years, Australia and New Zealand will be seen as a the pH of four different 0.9% saline preparations ranged from 5.35 – 5.95, and the pH of four 5% dextrose model of how to advance the science and practice of 2 Critical Care Medicine. preparations was even lower (4.2 – 4.85). The acidity of dextrose solutions has been variously attributed to 3 dissolved atmospheric CO2, the production of small Dr. R. Bellomo 3 4 Chairman, ANZICS Clinical Trials Group amounts of sugar acids, inherent acidity, caramelisation during autoclaving,5 pH adjustment by Department of Anaesthesia and Intensive Care 6 Austin and Repatriation Medical Centre the manufacturer in order to prevent caramelisation, or VICTORIA 3084 pH adjustment by the manufacturer to facilitate sterilisation and otherwise improve the stability of 7 REFERENCES dextrose preparations. Dissolved atmospheric CO2 is 1. Sackett DL, Rosenberg WM, Gray JM, Haynes RB, also the usual explanation proffered for the acidity of 3 Richardson WS. Evidence-based medicine: what it is saline preparations. and what it isn’t. BMJ 1996;312:71-72. For years the causes and significance of the low pH 2. Bellomo R. Prospective controlled randomized of crystalloid fluids has been a confusing topic, hence multicentre studies in Australasian Intensive Care Units: beloved of College examiners in basic science. What is folly or necessity? In Keneally J, Jones M (eds) commonly overlooked is that the titratable acidity of Australasian Anaesthesia 1996;pp 25-30. these crystalloids is minuscule. For example, the 3. Bellomo R, Bersten AD, Boots RJ, et al. The use of antimicrobials in ten Australian and New Zealand titratable acidity of the aforementioned 0.9% saline Intensive Care Units. Anaesth Intens Care 1998;26:648- preparations (defined as the concentration of titratable 653. hydrogen ion required to bring the pH to 7.4) ranged

10 Critical Care and Resuscitation 2000; 2: 7-13 EDITORIALS from 0.126 - 0.152 mEq/L.2 This is so low that when include thermal coagulation,11 enhancement of chemo- 0.9% saline is added to blood in vitro at pH = 7.4, there therapy and other oncological treatments,14-17 and in is only a very slight pH reduction. The rule holds true histopathology.18 The application stimulating the even with significant dilutions (e.g. 1:1 vol:vol) because interest of Drs Steele and Story is the use of microwave of the large buffering capacity of blood, provided there technology in warming fluids for intravenous is no change in haemoglobin-oxygen saturation - a fact administration and lavage.19 This has additional alluded to previously in this journal.8 The acidity of relevance to an article on accidental or therapeutic crystalloid fluids such as saline will thus not cause local hypothermia also in the current issue.20 Here Drs venous damage on infusion. Nonetheless, significant Connolly and Worthley reveal that peritoneal lavage metabolic acidosis can still result from the in vivo with dialysate at 44°C during the attempted reversal of infusion of 0.9% saline.9 This has nothing to do with the hypothermia transfers heat as efficiently as intrinsic pH of the infusion fluid and everything to do extracorporeal techniques. Although heating with alteration of the pCO2/pH relationship as a intravenous fluids to 41°C makes only a relatively small consequence of altered buffer base concentration (strong contribution to rewarming, efficient and accurate 10 ion difference). warming of resuscitation fluids during large volume Drs Steele and Story have now added another resuscitation, such as in burns or major trauma is tentative explanation for these small amounts of important to prevent heat loss. Which leads us to ask titratable acid in commercial preparations of normal whether anything is to be gained from employing saline - that of acid release by the PVC packaging. They microwave technology as a means of heating fluids for advance this possibility on fairly tenuous evidence - the resuscitation and lavage. What are its advantages and demonstration of differences in the pH of 100 mL and 1 disadvantages compared with the more conventional litre bags which are unaffected by microwave heating. devices such as incubators, waterbaths, thermal jackets The most obvious deficiency with this reasoning is that and countercurrent heat exchange units? they have not yet proved that saline in 100 mL bags is Firstly, the question of plasticiser toxicity raised by always more acidic than saline in 1 litre bags. Many Drs Steele and Story needs to be dealt with. DEHP is in batch numbers need to be tested to confirm it is a bag common use as a plasticiser in the PVC of commercial volume specific rather than a batch specific IV bags and lines. It is known to leach into intravenous phenomenon. Bags from different manufacturers also fluids, particularly during high intensity blood - PVC need evaluation. Even if the phenomenon is found to be interactions such as extracorporeal circuits.21,22 consistent, PVC packaging seems an unlikely culprit. Although many potential toxic effects have been The fact that the pH range of 5% dextrose quoted by ascribed to DEHP and its metabolite mono(2- one manufacturer is the same whether it is packaged in ethylhexyl) phthalate (MEHP), including lipid glass or PVC (pH = 3.5 - 6.5, Baxter, Australia) peroxidation of stored erythrocytes,23 cardiotoxicity,24 certainly fails to support the proposition. The authors’ hepatotoxicity25 and pulmonary toxicity,26 the jury is conclusion that ‘no further acids are released’ as a result still out on whether plasticiser leaching is a genuine of microwave heating would be better stated simply as problem in normal clinical scenarios.22 What does seem ‘no acids are released’. definite is that microwave heating of PVC packaged Is this interest in microwave heating of fluids fluids does not increase the risk of DEHP exposure relevant to critical care practice? Do microwaves have compared with other heating techniques.13, 27,28 There is special properties of use to intensivists? Microwave also no clear evidence that microwaves cause direct energy is a form of non-ionising electromagnetic tissue damage in the absence of a significant radiation, with a frequency of 300 MHz to 3 × 106 MHz temperature rise. No particular antimicrobial propensity - between radiofrequency and infrared in the has been identified beyond that of heating.29 electromagnetic spectrum.11 When substances are The main advantage of microwave heating is speed. traversed by microwave radiation, warming occurs by For example, 1 litre bags of crystalloid at 21°C can be production of molecular vibration in dipoles. Liquid heated to 32°C, 45°C and 53°C in 2, 4 and 5 minutes water is therefore an ideal medium for microwave respectively.30 Units of fresh frozen plasma can be 12 heating. Substances with low dielectric properties such thawed in a microwave oven in 5 to 8 minutes, as as plastics and ceramics do not absorb energy from compared with 20 to 30 minutes in a 37°C circulating microwaves, and will undergo a temperature increase by water bath.13 Potential benefits arising from this kind of conduction from contained fluids. Similarly, ice absorbs heating efficiency during urgent intravenous microwaves poorly, and is thawed during microwave resuscitation are self-evident. However, there is a irradiation mainly by contact with adjacent heated 13 downside. There are no universally applicable heating water. formulae, and ovens need individual calibration. It is Medical applications of microwave technology also wise to check the temperature of all fluids before

11 EDITORIALS Critical Care and Resuscitation 2000; 2: 7-13 infusion, as thermal injury at a peripheral infusion site 2. Lebowitz MH, Masuda JY, Beckerman MS. The pH and has been reported.31 It is usual to restrict the temperature acidity of intravenous infusion solutions. JAMA of infused fluids to 41°C to avoid haemolysis, especially 1971;215:1937-1940. during peripheral administration. 3. Kautz HD, Parker EA. pH of intravenous solutions. N Engl J Med 1969;280:901-902. Another problem is the uneven nature of the heat 4. Kosler AW. pH of intravenous solutions. N Engl J Med exchange process, with the creation of ‘hot spots’. In the 1969;280:901. case of fresh frozen plasma, precipitation of plasma 5. Klimpel D, Cohon MS. pH of intravenous solutions. N proteins and loss of coagulation factors can result, even Engl J Med 1969;280:900-901. when short pulses of irradiation are interspersed with 6. Heller WH. pH of intravenous solutions. N Engl J Med pauses to allow redistribution of heat.13 Blood units can 1969;280:901. develop gross haemolysis in areas of local 7. Weiss EB, Sewell D. pH of intravenous solutions. N overheating,32 and at least one fatality connected with Engl J Med 1969;280:902. this phenomenon has been reported.33 The ‘hot spot’ 8. Morgan TJ. Finding common ground in acid-base [Editorial]. Critical Care and Resuscitation 1999;1:123- problem can be reduced if bags are rotated or agitated 126. during irradiation. Shielding of spike ports and the 9. Scheingraber S, Rehm M, Sehmisch C, Finsterer U. tapered ends of IV bags is also useful. In a purpose- Rapid saline infusion produces hyperchloremic acidosis made device with the further modifications of a in patients undergoing gynecologic surgery. temperature sensor and automatic shut-off at 21°C, safe Anesthesiology 1999;90:1265-1270. and rapid thawing of frozen plasma without significant 10. Morgan TJ, Hall JA. Hyperlactaemia without acidosis - loss of coagulant activity has been demonstrated.34,35 an investigation using an in vitro model. Critical Care However, many hospital blood banks still use and Resuscitation 1999;1:354-359. 11. Kalabakas AA, Porter AJ, Mule L, Birch MJ, Pollock circulating water baths in preference to purpose-made DJ, Swain CP. Design of a microwave system for microwave devices to thaw frozen plasma, mainly to endoscopy: an experimental study of energy, tissue save money. contact and hemostatic efficiency. Gastroenterology Finally there has been a significant development in 1993;104:680-689. the rapid heating of red cell preparations for intravenous 12. Schwan HP, Foster KR. Microwave dielectric properties infusion – the in-line microwave blood warmer.36-38 In of tissues: some comments on the rotational mobility of an in vitro study a group from Boston has shown the tissue water. Biophys J 1977;17:193-197. heating performance of in-line microwave blood 13. Luff RD, Kessler CM, Bell WR. Microwave technology warming devices to be better at high flow rates for the rapid thawing of frozen blood components. Am J Clin Pathol 1985;83:59-64. (exceeding 500 mL/minute) than that of state of the art 37 14. Howard GC, Bleehan NM. Clinical experience in the single channel countercurrent heat-exchangers. Indices combination of hyperthermia with chemotherapy or of haemolysis did not increase with either type of radiotherapy. Recent Results Cancer Res 1988;107:214- warming device at this flow rate. Because lower flow 221. rates are associated with longer in-line exposure times, 15. Dubois JB, Hay M, Bordure G. Superficial microwave- there is an increased haemolysis potential. However, induced hyperthermia in the treatment of chest wall here again haemolysis was minimal and not worse than recurrences in breast cancer. Cancer 1990;66:848-852. that associated with the conventional heat-exchanger. 16. Henderson BW, Waldow SM, Potter WR, Dougherty TJ. The same research group has now published evidence Interaction of photodynamic therapy and hyperthermia: tumour response and cell survival studies after treatment that blood heated to temperatures as high as 49°C 38 of mice in vivo. Cancer Res 1985;45:6071-6077. remains haemolysis-free using these in-line devices. 17. Finger PT. Microwave thermoradiotherapy for uveal Clinical evaluation is awaited with interest. Apart from melanoma: results of a 10-year study. Opthalmology a need for recalibration, there would appear to be no 1997;104:1794-1803. reason why the technology could not be extended to the 18. Van de Kant HJ, Rooij DG, Boon ME. Microwave warming of rapidly infused crystalloids. stabilization versus chemical fixation. A morphometric study in glycolmethacrylate- and paraffin-embedded Dr. T. J. Morgan tissue. Histochem J 1990;22:335-340. 19. Handrigan MT, Wright RO, Becker BM, Linakis JG, Jay Intensive Care Facility GD. Factors and methodology in achieving ideal Royal Brisbane Hospital delivery temperatures for intravenous and lavage fluid in QUEENSLAND 4029 hypothermia. Am J Emerg Med 1997;15:350-353. 20. Connolly E, Worthley LIG. Therapeutic and accidental REFERENCES hypothermia. Critical Care and Resuscitation 2000;2:22- 1. Steele RG, Story DA. The effect of microwave heating 29. on the acidity of 0.9% saline in 1 litre and 100 mL 21. Karle VA, Short BL, Martin GR et al. Extracorporeal polyvinyl chloride packaging. Critical Care and membrane oxygenation exposes infants to the Resuscitation 2000;2:19-21.

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plasticizer, di(2-ethylhexyl) phthalate. Crit Care med 30. Anshus JS, Endahl GL, Mottley JL. Microwave heating 1997;25:696-703. of intravenous fluids. Am J Emerg Med 1985;3:316-319. 22. Faouzi MA, Dine T, Gressier B et al. Exposure of 31. Sieunarine K, White GH. Full-thickness burn and hemodialysis patients to di-2-ethylhexyl phthalate. Int J venous thrombosis following intravenous infusion of Pharm 1999;180:113-121 microwave-heated crystalloid fluids. Burns 23. Deepa Devi KV, Manoj Kumar V, Arun P et al. 1996;22:568-569. Increased lipid peroxidation of erythrocytes in blood 32. McCullough J, Polesky HF, Nelson C, Hoff T. stored in polyvinyl chloride blood storage bags Iatrogenic hemolysis: a complication of blood warmed plasticized with di-[2-ethylhexyl] phthalate and effects by a microwave device. Anesth Analg 1972;51:102-106. of antioxidants. Vox Sang 1998;75:198-204. 33. Staples PJ, Griner PF. Extracorporeal hemolysis of 24. Barry YA, Labow RS, Rock G et al. Cardiotoxic effects blood in a microwave warmer. N Engl J Med of the plasticizer metabolite mono(2-ethylhexyl) 1971;285:317-319. phthalate (MEHP) on human myocardium. Blood 34. Rock G, Tackaberry ES, Dunn JG, Kashyap S. Rapid 1988;72:1438-1439. controlled thawing of fresh-frozen plasma in a modified 25. Jacobsen MS, Kevy SV, Grand RJ. Effects of a microwave oven. Transfusion 1984;24:60-65. plasticizer leached from polyvinyl chloride on subhuman 35. Churchill WH, Schmidt B, Lindsey J, Greenberg M, primates. A consequence of chronic transfusion therapy. Boudrow S, Brugnara C. Thawing fresh frozen plasma J Lab Clin Med 1977;89:1066-1078. in a microwave oven. A comparison with thawing in a 26. Schulz CO, Rubin RJ, Hutchins GM. Acute lung toxicity 37°C waterbath. Am J Clin Pathol 1992;97:227-232. and sudden death in rats following the intravenous 36. Schwaitzberg SD, Allen MJ, Connolly KJ et al. Rapid administration of the plasticizer, di(2-ethylhexyl) in-line blood warming using microwave energy: phthalate, solubilized with tween surfactants. Toxicol preliminary studies. J Invest Surg 1991;4:505-510. Appl Pharmacol 1975;33:514-525. 37. Pappas CG, Paddock H, Goyette P, Grabowy R, 27. Sherman L, Thompson K, O'Kell RT. Phthalate levels in Connolly RJ, Schwaitzberg SD. In-line microwave microwave thawed fresh frozen plasma. Transfusion blood warming of in-date human packed red blood cells. 1982;22:401. Crit Care Med 1995;23:1243-1250. 28. Ausman RK, Kerkhof K, Holmes CJ et al. Frozen 38. Herron DM, Grabowy R, Connolly R, Schwaitzberg SD. storage and microwave thawing of parenteral nutrition The limits of bloodwarming: maximally heating blood solutions in plastic containers. Drug Intell Clin Pharm with an inline microwave bloodwarmer. J Trauma 1981;15:440-443. 1997;43:219-226. 29. Sheeran MR, Kerr KG, Dealler SF, Hayes PR, Lacey RW. Listeria survives microwave heating. J Hosp Infect 1989;14:84-86.

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